The Women's Health Initiative Clinical Trials (WHI-CT) found that hormonal therapy With combined estrogen and progestin (E+P), but not estrogen alone (E), significantly reduced the risk of colorectal cancer in postmenopausal women, However, the biologic mechanisms underlying the protective effect of E+P, and explaining its absence in E, are unknown. Indeed, little at all is known regarding the role of sex hormones in colore~t[unreadable]l tumorigenesis. We recently observed a significant positive association between endogenous estradiol levels and colorectal cancer among women enrolled in the WHI Observational Study. This finding, though consistent with in vitro data that demonstrate mitogenic effects of estradiol in the colon, requires validation in other study populations. Furthermore, no studies to our knowledge have assessed the relation of colorectal cancer with progesterone, the factor that most obviously distinguishes E+P from E. The primary objective of the proposed investigation is, therefore, to evaluate the association of incident colorectal cancer with estradiol, estrone, progesterone and sex hormone binding globulin among women enrolled in the untreated arms of the WHI-CT (women not using E or E+P). Using established methods, we will measure these hormonal factors in 400 incident colorectal cancer cases and 800 matched controls. Determining the role of sex hormones in the development of colorectal cancer is essential to understanding the protective effects of E+P and, from a scientific perspective, wil provide insight into previously uncharacterized carcinogenic pathways.